Chemoattractants acting through their cognate receptors are critical for the recruitment of effector immune cells to inflamed tissues, and are therefore of considerable interest as potential targets for the treatment of inflammatory disease. CCRL2 (also known as HCR, CRAM-A and CRAM-B) encodes an orphan chemokine receptor-like protein, which is predicted to be a seven transmembrane protein. G protein coupled receptors (GPCRs) are a family of approximately 500 proteins with a 7 transmembrane structure that are involved in variety of biological functions.
For classical chemoattractant receptors, interaction with its cognate ligand causes a conformational change in the protein and facilitates the binding of small associated heterotrimeric G proteins to the intracellular receptor domains, which initiate a signaling cascade. ‘Atypical’ chemoattractant receptors bind to chemoattractants but do not transduce intracellular signals leading to cell migration. This functionally defined receptor subfamily is currently comprised of three members-D6, DARC (Duffy antigen receptor for chemokines), and CCX-CKR (Chemocentryx chemokine receptor). The receptors are also referred to as professional chemokine “interceptors”, a name that reflects their ability to efficiently internalize bound ligand.
Despite recent advances, cancer continues to be a leading cause of mortality worldwide. Harnessing a patient's immune system to destroy cancer cells is a promising therapeutic strategy. However, most current cancer immunotherapies selectively activate a limited repertoire of immune defenses and often have incomplete efficacy. A major immune evasion strategy of cancer cells is the establishment of an immunosuppressive tumor microenvironment through the selective recruitment of M2 macrophages, myeloid-derived suppressor cells (MDSCs) and tolerogenic DCs, and the exclusion of anti-tumor immune cells such as natural killer (NK) cells, M1 macrophages and immunostimulatory DCs. However, the underlying cell trafficking mechanisms that govern this process are incompletely understood.
Chemerin is a chemoattractant that is downregulated in several cancers including melanoma, prostate, lung, breast and colon cancer. Chemerin is produced and released by hepatocytes, endothelial cells, fibroblasts, adipocytes, epithelial cells, platelets and chondrocytes. Upon proteolytic processing, chemerin is activated and binds the G-protein coupled receptor chemokine receptor-like 1 (CMKLR1), which is expressed on several immune cells, in particular NK cells.
A second chemerin-binding receptor, CC-chemokine receptor-like 2 (CCRL2) is primarily expressed on endothelial cells, activated macrophages, and mast cells. Unlike CMKLR1, CCRL2 does not internalize or trigger intracellular calcium mobilization upon binding chemerin. Instead, CCRL2 binds chemerin with high affinity and presents it on the cell surface. The present invention provides for a role of CCRL2 in cancer progression.